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c h a p t e r f o u r t e e n The ‘‘Gold Standard’’ Estrogen and the Randomized Controlled Trials Estrogen underwent yet another reversal of fortune in July 2002. That month, the Women’s Health Initiative—the multiyear, multisite, multimillion-dollar, federally funded clinical trial of hormone replacement therapy—was stopped three years before its scheduled endpoint, because the study’s Data and Safety Monitoring Board concluded that the risks of adverse e√ects outweighed the benefits of continuing the study. The risk of breast cancer, in particular, exceeded the predetermined limit of safety; additionally, women taking the estrogen-progestin pills were at increased risk for heart attacks, strokes, and blood clots. Letters were sent to the sixteen thousand study participants with instructions to discontinue use of the drugs. The story made the front pages of newspapers across the country and was reported on national television news broadcasts, because it a√ected the lives of the millions of American women who were using or thinking about using HRT.∞ This development flew in the face of accepted medical practice in the United States and threw the consumers of monthly prescriptions of this received wisdom into a state of panic. The shock waves from this report traveled quickly. In rapid response to the news, the price of Wyeth’s stock fell by more than 24 percent.≤ A survey of physicians taken ten days after the release of the report found that they had told about half of their patients to stop taking Prempro or to switch to an alternative treatment.≥ Within a year, prescriptions for Prempro dropped by 33 percent, Premarin ’s plummeted by 66 percent, and the total number for all brands of HRT declined by more than a third.∂ The fallout from the Women’s Health Initiative (WHI) was both immediate and long lasting, but it was also confusing and contested. The WHI was not, however, the first indication of bad news about estrogen. Four years earlier, in August 1998, a di√erent randomized controlled trial, the Estrogen and the Randomized Controlled Trials 265 Heart and Estrogen/Progestin Replacement Study (HERS), found that hormone replacement therapy did not reduce the rate of heart attacks in women who already had coronary disease. Funded by Wyeth-Ayerst, the maker of Premarin and Prempro, this four-year study of more than twenty-seven hundred women cast the initial shadow on the alleged cardio-protective benefits of estrogen. The genesis of the HERS trial was intertwined, although unintentionally, with that of the WHI, back in 1992. A group of researchers at the University of California, San Francisco, decided that it was time to put the hypothesis that estrogen reduced the risk of heart disease to the ‘‘gold standard’’ test of a randomized , double-blind, placebo-controlled clinical trial. (The PEPI trial had been a randomized controlled trial, but it had only measured intermediate outcomes, such as blood lipid levels; a more conclusive study would actually evaluate disease outcomes.) These investigators, proponents of the movement toward evidencebased medicine (the application of the scientific method to medical practice), wanted to design a study that would either confirm or refute the evidence from observational studies that correlated postmenopausal estrogen use with lower rates of heart disease. Some of them had been involved in writing the guidelines on hormone replacement therapy for the American College of Physicians, and they had felt uneasy about basing their recommendation that all women consider preventive use of HRT on observational, as opposed to experimental, evidence.∑ The group wrote a proposal for a large-scale trial to be conducted at medical centers around the country, recruiting a cadre of well-known, experienced investigators to participate in carrying out the work. As a ‘‘secondary prevention trial,’’ the study would test the e√ect of hormone therapy in women who already had coronary heart disease. If estrogen could prevent heart attacks in these high-risk women, then it could be concluded that the drug would have a similar benefit in the larger population of postmenopausal women, as a ‘‘primary preventive’’ of heart disease. Some people believed that such a trial should not be done, because it would be unethical to randomize women to placebo, thereby denying them the presumed benefits of hormone therapy. Indeed, the investigators had high hopes that the randomized trial would substantiate what they accepted as persuasive evidence: the strength and consistency of the observational data—dozens of studies had found...

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